In vivo neuronal deficits and microglia structural dynamics in the course of tau pathology and during antibody treatment

Abstract

AbstractBackgroundWe crossed mouse models Thy‐1GCaMP6, Cx3cr1CreER:tdTomatoflox and Cx3cr1GFP with PS19 P301S tauopathy mice to visualize neuronal calcium and microglia structural dynamics in vivo during the progression of tau pathology and after tau immunotherapy.MethodBy using two‐photon live imaging in head‐restrained mice attached to a custom‐made, free‐floating treadmill, we examined calcium activity in L2/3 pyramidal neurons and microglia structural dynamics in the motor cortex during tau pathology progression and after two intravenous antibody injections targeting the truncated Asp421 epitope of tau.ResultL2/3 pyramidal neurons from young Thy‐1GCaMP6:wild‐type mice (1‐6 months old) increased their somatic activity during running periods as expected, but their littermate Thy‐1GCaMP6:PS19+/− mice did not. Importantly, acute tau immunotherapy restored neuronal function after two intravenous antibody injections (100 µg each) in Thy‐1GCaMP6:PS19+/− mice (5‐6 months old), whereas control antibody had no effect. Although tau pathology is evident in the cortex and hippocampus in 2‐3 months old Cx3cr1GFP/+:PS19+/− mice and Cx3cr1CreER/+:tdTomatoflox:PS19+/− mice, their microglia morphology did not differ from control littermate Cx3cr1GFP/+:wild‐type mice.ConclusionOur current findings indicate that functional deficits in cortical neurons associated with tau pathology start early in PS19 mice and can be alleviated by two acute tau antibody injections. Also, those neuronal functional impairments can be detected without accompanying structural changes in microglia, which suggests that neuronal deficits linked to tau accumulation precede microglial activation. Studies on the potential influence of tau antibody treatment on microglia morphology in vivo are underway.